The present invention relates to compounds of general formula (I) 
wherein the groups A, Het, R1, R2, and R3 may have the meanings given in the following description and in the claims, processes for preparing them and the use of compounds of general formula (I) as pharmaceutical compositions, particularly as pharmaceutical compositions with a beta-amyloid-inhibiting activity.
The aggregation and precipitation of proteins are implicated in the origins of various neurodegenerative disorders such as Alzheimer""s, Parkinson""s, and St. Vitus"" dance (xe2x80x9cHuntington""s Choreaxe2x80x9d). In Alzheimer""s disease, the amyloid-xcex2-peptide (Axcex2) aggregates and leads to insoluble senile plaques which constitute one of the pathological markers of the disease. Axcex2 is formed by the proteolytic cleaving of a precursor protein, amyloid precursor protein (APP). Two methods of metabolizing APP have been detected, the non-amyloidogenic method and the amyloidogenic method.
In the non-amyloidogenic metabolism of APP, xcex1-secretase cleaves within the Axcex2 region of the APP and thus leads to the secretion of the soluble N-terminal region of the protein (xcex1-APPs) and, after the xcex3-secretase cutting has taken place, to the release of p3. By contrast, the amyloidogenic route leads to the formation of AP, two proteases generating the N-terminus (xcex2-secretase), and the C-terminus (xcex3-secretase), respectively, of Axcex2.
Axcex2 can be detected in human plasma and cerebrospinal fluid in vivo. In cell culture, too, secreted Axcex2 can be detected in the cell culture supernatant of various types of cells which express or overexpress APP or fragments thereof endogenously.
The problem of the present invention is to prepare compounds which are capable of interfering (preferably in an inhibitory capacity) in the process of the formation of Axcex2 or its release from cells, or of reducing the activity of Axcex2 by inhibiting it. Finally, the present invention is based on the further objective of preparing compounds which can be used effectively for the prevention or treatment of Alzheimer""s disease.
The problems set forth above are solved by the compounds of general formula (I) defined as follows.
The compounds according to the invention are compounds of general formula (I) 
wherein
A denotes xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94;
Het denotes piperidinyl, piperazinyl, or dihydrobenzimidazolonyl;
R1 denotes hydrogen or halogen, preferably hydrogen;
R2 denotes hydrogen, C1-C4-alkyl, CF3, or a phenyl group which may optionally be substituted by halogen, C1-C4-alkyl, or C1-C4-alkyloxy; and
R3 denotes hydrogen, C1-C4-alkyl, HOxe2x80x94C1-C4-alkyl, C2-C4-alkenyl, or a group selected from among phenyl, benzyl, and phenylethyl, which may optionally be substituted by halogen, CF3, C1-C4-alkyl, or C1-C4-alkyloxy, or a heterocycle selected from among morpholine, piperidine, piperazine, and dihydrobenzimidazolone, which may be linked directly or via a C1-C4-alkylene bridge.
Preferred compounds of general formula (I) are those wherein:
A denotes xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94;
Het denotes piperidinyl, piperazinyl, or dihydrobenzimidazolonyl;
R1 denotes hydrogen or halogen, preferably hydrogen;
R2 denotes hydrogen, C1-C4-alkyl, phenyl, halogen-substituted phenyl, C1-C4-alkyloxy-substituted phenyl, or CF3; and
R3 denotes C1-C4-alkyl, HOxe2x80x94C1-C4-alkyl, C2-C4-alkenyl, phenyl, benzyl, phenylethyl, halogen-substituted phenyl, halogen-substituted benzyl, or a heterocycle selected from among morpholine and dihydrobenzimidazolone, which may be linked directly or via a C1-C4-alkylene bridge.
Particularly preferred compounds of general formula (I) are those wherein:
A denotes xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94;
Het denotes piperidinyl, piperazinyl, or dihydrobenzimidazolonyl;
R1 denotes hydrogen or chlorine, preferably hydrogen;
R2 denotes hydrogen, methyl, phenyl, or 4-chlorophenyl; and
R3 denotes C1-C4-alkyl, HOxe2x80x94C1-C4-alkyl, C2-C4-alkenyl, phenyl, benzyl, halogen-substituted benzyl, or a heterocycle selected from morpholine and dihydrobenzimidazolone, which may be linked directly or via a C1-C4-alkylene bridge.
Of particular importance according to the invention are compounds of general formula (I), wherein:
A denotes xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94;
Het denotes piperidinyl or piperazinyl;
R1 denotes hydrogen or chlorine, preferably hydrogen;
R2 denotes hydrogen, methyl, phenyl, or 4-chlorophenyl; and
R3 denotes 2-hydroxyethyl, phenyl, benzyl, 4-chlorobenzyl, or 1,3-dihydrobenzimidazol-2-on-1-yl.
Also preferred are compounds of general formula (I) wherein:
A denotes xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94;
Het denotes piperidinyl or piperazinyl;
R1 denotes hydrogen;
R2 denotes hydrogen, methyl, phenyl, or 4-chlorophenyl; and
R3 denotes benzyl, 4-chlorobenzyl, or 1,3-dihydrobenzimidazol-2-on-1-yl.
Of exceptional importance according to the invention are the compounds of general formula (I), wherein the group xe2x80x94Hetxe2x80x94R3 denotes 
The compounds listed below are mentioned as being particularly important within the scope of the present invention:
(a) 1-{1-[2-(2-methylimidazo[1,2-a]pyridin-3-yl)ethyl]piperidin-4-yl}-1,3-dihydrobenzimidazol-2-one;
(b) 1-[1-(3-imidazo[1,2-a]pyridin-3-ylpropyl)piperidin-4-yl]-1,3-dihydrobenzimidazol-2-one;
(c) 1-[1-(2-imidazo[1,2-a]pyridin-3-ylethyl)piperidin-4-yl]-1,3-dihydrobenzimidazol-2-one; and
(d) 1-{1-[3-(2-phenylimidazo[1,2-a]pyridin-3-yl)propyl]piperidin-4-yl}-1,3-dihydrobenzimidazol-2-one.
The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids, such as, for example, acid addition salts with hydrohalic acids, e.g., hydrochloric or hydrobromic acid, or organic acids, such as oxalic, fumaric, diglycolic, or methanesulfonic acid.
The term alkyl groups (including those which are part of other groups) denotes branched and unbranched alkyl groups with 1 to 4 carbon atoms, unless otherwise specified. Examples include: methyl, ethyl, propyl, and butyl. Unless otherwise stated, the above terms propyl and butyl also include all the possible isomeric forms. For example, the term propyl also includes the two isomeric groups n-propyl and isopropyl and the term butyl includes n-butyl, isobutyl, sec-butyl, and tert-butyl. In some cases common abbreviations are also used to denote the abovementioned alkyl groups, such as Me for methyl, Et for ethyl, etc.
The term alkylene groups denotes branched and unbranched alkylene bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene, and butylene. Unless otherwise stated, the terms propylene and butylene used above also include all the possible isomeric forms. Accordingly, the term propylene also includes the two isomeric bridges n-propylene and dimethylmethylene and the term butylene includes the isomeric bridges n-butylene, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.
The term alkenyl groups (including those which are part of other groups) denotes branched and unbranched alkenyl groups with 2 to 4 carbon atoms, provided that they have at least one double bond, such as, for example, vinyl (provided that no unstable enamines or enolethers are formed), propenyl, isopropenyl, and butenyl.
The term halogen generally denotes fluorine, chlorine, bromine, or iodine. Unless otherwise specified, chlorine is preferred within the scope of the present invention.
xe2x80x9cxe2x95x90Oxe2x80x9d denotes an oxygen atom linked via a double bond.
In the definitions given above, all the definitions given for the groups A and Het according to general formula (I) should be regarded as double-bonded groups. The groups A, unless they are the asymmetric bridge members xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, should be linked to their neighboring groups in two different orientations. The preferred orientation according to the invention is the one in which the carbonyl function of the bridge members mentioned above is bonded directly to the group xe2x80x9cHetxe2x80x9d. The group Het may also be linked to its neighboring groups in various orientations. The preferred orientation according to the invention is the one in which the group Het is linked by at least one nitrogen atom to the bridge A. Most preferably, the groups piperazinyl and dihydrobenzimidazolonyl defined as Het groups are also linked to the group R3 via their second N atom.
By dihydrobenzimidazolonyl is meant 1,3-dihydrobenzimidazol-2-on-1-yl.
According to another aspect, the present invention relates to the use of the compounds of general formula (I) defined above as pharmaceutical compositions. In particular, the present invention relates to the use of the compounds of general formula (I) for preparing a pharmaceutical composition for the prevention and/or treatment of diseases in which a therapeutic benefit can be achieved by interfering (preferably in an inhibitory capacity) in the process of the formation of Axcex2 or its release from cells. It is preferred according to the invention to use compounds of general formula (I) as specified above in order to prepare a pharmaceutical composition for the prevention and/or treatment of Alzheimer""s disease.
One approach to synthesizing the compounds of general formula (I) according to the invention may involve the use of various methods, optionally based on or using conventional chemical methods of synthesis as described in more detail hereinafter.
One possible method of synthesizing the compounds of general formula (I) wherein A denotes an ethylene bridge is shown in Diagram 1. 
Diagram 1:
In a first step (stage A) a 2H-imidazo[1,2-a]pyridine (II) is converted, by reaction with N,N-dimethylmethyleneiminium chloride, into the aminomethyl-substituted compounds (III) from which the quaternary ammonium salts (IV) can be obtained by alkylation with methyl iodide (stage B). These can then be converted into the nitrites (V) (stage C), which when hydrolyzed yield the carboxylic acid esters (VI) (stage D). Reduction of the compounds (VI) according to stage E leads to the alcohols (VII) which are converted in stage F into the halides (VIII). The compounds of formula (I) wherein A denotes xe2x80x94CH2xe2x80x94CH2xe2x80x94 may be obtained therefrom by nucleophilic substitution (stage G).
As an alternative to the synthesis strategy outline in Diagram 1 the compounds of formula (VII) may also be obtained according to Diagram 2. 
Diagram 2:
For this, the 2H-imidazo[1,2-a]pyridines (II) are converted in a Vilsmeier reaction into the formylated 2H-imidazo[1,2-a]pyridines (IX) (stage H). From these, the olefins (X) can be obtained by Wittig reaction (stage I). The alcohols (VII) may be obtained according to stage J by hydroboration of the compounds (X).
Another variant of the process enables the compounds of formula (VI) to be obtained in a different manner from Diagram 1. This is shown in Diagram 3. 
Diagram 3:
Starting from the carbonyl compounds (XI), the xcex1-bromocarbonyl compounds (XII) may be obtained by bromination (stage K). After reaction with 1-aminopyridines of formula (XIII) these compounds (XII) lead to the esters (VI) (stage L).
Compounds of formula (I) wherein A denotes the bridge xe2x80x94CH2xe2x80x94COxe2x80x94 may be obtained from the esters of formula (VI) by an alternative method to that shown in Diagram 1. They may then in turn be converted into compounds of formula (I) wherein A denotes xe2x80x94CH2xe2x80x94CH2xe2x80x94 (Diagram 4). 
Diagram 4:
The saponification of the esters (VI) leads, according to stage M, to the free carboxylic acids (XIV). These may optionally be converted according to stage N by reacting with the amines Hxe2x80x94Hetxe2x80x94R3, using suitable coupling reagents, into the corresponding amides (I, where A is xe2x80x94CH2xe2x80x94CO), which can be reductively transformed into the corresponding compounds of formula (I) wherein A equals xe2x80x94CH2xe2x80x94CH2xe2x80x94 (stage O).
For preparing compounds of formula (I) wherein A denotes xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, the procedure illustrated in Diagram 5 may be used. 
Diagram 5:
Starting from the carbonylated compounds (IX) the xcex1,xcex2-unsaturated esters (XV) are synthesized by a Wittig or Wittig-Homer-Emmons reaction (stage H). If the esters (XV) according to stage M are saponified to form the carboxylic acids (XVI), these may be converted according to stage N into the xcex1,xcex2-unsaturated amides (I, where A is xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94). From these, the compounds of formula (I) wherein A denotes propylene can be obtained reductively (stage R). Alternatively, the latter may be obtained by reduction (stage Q) of the esters (XV) to form the alcohols (XVII), which give access to the target compounds by standard methods (stages F and G) via the halides (XVIII).
Another alternative process (cf. Diagram 6) provides a method of obtaining the compounds of formula (XVII) different from that shown in Diagram 5 and on the other hand yields the compounds of formula (I) wherein A denotes xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94. 
Diagram 6:
Starting from the carbonyl compounds (XIX) bromination produces the xcex1-bromocarbonyl compounds (XX) (stage K), which when reacted with 1-aminopyridines of formula (XIII) provides access to the esters (XXI) (stage L). These may be converted, on the one hand, according to stage E, into the alcohols (XVII), while on the other hand, after saponification (stage M) to yield the carboxylic acids (XXII), they may also be used as starting compounds for preparing the compounds of formula (I) wherein A denotes xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94. The latter may be converted reductively, analogously to stage O (cf. Diagram 4), into the compounds of general formula (I) wherein A denotes xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94.
In the methods of synthesis described above it may be appropriate to use common protecting groups which may be both introduced and cleaved by standard methods.
The examples of synthesis which follow are intended only as an illustration without restricting the object of the invention.